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The Indian Health Service technique has demonstrated – in a single moderate quality (pragmatic, non-randomized, unblinded, multicenter prospective trial) of 500 participants – to be superior to traditional lecture-style technique in ambulatory non-pregnant adults being able to immediately recall medical information after a single counseling session from a pharmacist

Outcomes

71% of the IHS method group successfully recalled medication information vs 33% for the traditional method group

Odds of patients knowing when to take their medication and its side-effects profile were about 4 times more likely to happen in the IHS vs the traditional group

IHS pharmacists were bringing up side-effects approximately 3 times more often in their counseling.

The time required for both groups were 128 and 75 seconds for IHS and traditional, respectively

Although promising, the IHS method should be further studied to assess whether it can improve other measures such as long-term adherence, clinical targets; as well as medication-related mortality, morbidity, and health system expenditures

The method developed by IHS pharmacists is described by Lam et al. in a recent study which is the subject of this article (fig:1) :

“The second method is the Indian Health Service (IHS) technique, which uses three open-ended questions (prime questions) to verify patient understanding of the name and purpose of the medication, directions for use and storage, what to expect if the medication works, what to do if it does not, and what type of potential adverse effects to look out for, as well as what to do if they should occur. Any gaps in understanding are corrected before moving on to the next prime question. After completing the prime questions, patients are asked to verbally confirm their understanding of the information discussed during the three prime questions (Figure 1). When patients verbalize their understanding by answering the three prime questions and during final verification, the information is placed in longer term or gist memory and is retained longer than the information patients hear in the traditional counseling method.”

Non-pregnant adults were asked to participate in the study by a pharmacy technician and were led to a private room where the pharmacist consultation would take place. There was an investigator in the room present to accurately measure the counseling time and the pharmacist in the room did not know which patient were included in the study, nor which question the patient would be asked immediately afterwards in an interview. In the control group (traditional method), the pharmacist would present verbal information containing the name of the drug, how to take it, and possible adverse effects; while the intervention group (IHS method) were trained to provide structured and open-ended questions to verify patient understanding of the proper use of the new prescription medication (see Fig.1).

Results and limitations

In total, 500 participants were included in the study. It is noted that the IHS group were generally younger, had been using the study pharmacy for a shorter amount of time, and had been prescribed more contraceptives and less cardiovascular medications than the control group. The main outcome was correct recall answers for all three questions concerning their new prescription – the Indian Health Service intervention group yielded a 71% accuracy compared to 33% for the traditional method. Also, the odds of knowing when to take their medication and its side-effects profile were about 4 times more likely to happen in the IHS than the traditional group. Even the IHS pharmacists were bringing up side-effects approximately 3 times more often in their counselling. Lastly, the time required for both groups were 128 and 75 seconds for IHS and traditional, respectively.

A few limitations in the study’s methodology affects their findings: it was not a randomized sample of participants; blinding was mostly impossible, especially of the counselling pharmacist; no surrogate (like blood pressure) or adherence (pill-count devices) outcomes were assessed; and no later-recall (e.g.: 24-hour or 1 month post-counselling) was measured. This last limitation is important because counselling techniques need to show that patient education can reliably be improved upon in terms of long-term adherence since many medication-related hospitalizations are due to chronic medications (e.g.: anticoagulants, digoxin, insulin). Hopefully, the end result of would be that improving the patient’s long-term adherence by the IHS technique could subsequently increase the efficacy of treatments prescribed while reducing mortality, morbidity, and overall health-care expenditures caused by poor adherence.

The other issues seen with this study mostly are attributed to disadvantages of using convenience sampling (or non-probability sampling) which limits the generalizability of the study. If the study participants are chosen from a convenient sample, and not from the total population, there is a risk of selection bias and sampling error – specifically the intervention group may differ largely in certain characteristics from the control group which may confound the results. For example, we must take into consideration that the intervention group were on average 10 years younger and may have better recall ability or otherwise test better than the control group.

Conclusion

Considering that both groups were relatively similar and the magnitude of the effect seen, we can conclude that the results of Lam et al. are valid and certainly make the case for further studies using other outcomes to determine if the Indian Health Service method is truly a counselling gold standard.

The US Federal Drug Agency (FDA) Antimicrobial Drugs Advisory and the Drug Safety and Risk Management Advisory Committees met in early november (1, 2) to discuss the effectiveness and safety of systemic fluoroquinolones (FQs) antibiotics for the currently approved indications of acute bacterial sinusitis (ABS), acute bacterial exacerbation of chronic bronchitis in patients who have chronic obstructive pulmonary disease (ABECB-COPD), and uncomplicated urinary tract infections (uUTIs). The meeting saw presentations from both the FDA and the pharmaceutical industry (and also heard from patients who were prescribed FQs) whereafter panel members voted on questions concerning whether the indications are supported by clinical evidence in light of new post-marketing surveillance data.

This review comes after the FDA required (Black) Boxed Warnings in FQ monographs for tendinitis and tendon rupture in 2008, and also for an association of peripheral neuropathy in 2013. The new safety issues – a constellation of symptoms termed fluoroquinolone-associated disability (FQAD) – are an example of the importance of post-marketing surveillance when very rare side-effects, which may or may not have been apparent in a relatively small sample of patients in pre-market clinical trials, are magnified after being approved for sale in the general population. In this case, the committees were presented data showing there still may be a problem of over-prescribing FQs for the following illness-specific reasons:

randomized trials in ABS and mild cases of ABECB-COPD show a large proportion of patients in placebo group recovered similarly to the respiratory FQ treatment arm and as such can be considered self-limiting illnesses in many cases (2)

recent international guidelines of uUTIs favor using potentially safer alternatives such as nitrofurantoin and sulfamethoxazole-trimethoprim (see Fig.1).

Figure 1: Treatment algorithm for uUTIs, from the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases (3)

The committees also made recommendations aimed at manufacturers and other stakeholders such as:

Manufacturers: product labeling with more specific language indicating use as second line therapy ; incorporation of treatment guidelines put forth by professional societies; including language that describes the constellation of adverse effects identified as Fluoroquinolone-Associated Disability (FQAD); removing language identifying susceptible microorganisms and adding language stating that a positive culture should be obtained prior to initiating treatment with a fluoroquinolone (for ABECB-COPD)

Prescribers and Patients: adding a REMS program to the fluoroquinolones ranging from a Medication Guide to required education for prescribers and patients

Professional Societies: change of drug labeling such as requiring urine cultures may be an important consideration for future guidelines in treating adult patients (uUTIs)

Figure 2: Treatment algorithm for ABECB-COPD by Canadian Thoracic Society and the Canadian (5)

Given the limited benefits and the new potential safety risks reported as FQAD, the joint committees voted that fluoroquinolones are not supported for the currently labeled indications for the treatment of ABS, (mild) ABECB-COPD, or uUTI. The FDA has mentioned important caveats: first, there is robust evidence of effectiveness for moderate to severe ABECB-COPD and is often warranted in hospitalised patients (5, fig.2). Also, using FQs of uUTIs are effective for microbiological eradication of bacteria and resolution of symptoms, but ibuprofen-controlled trials showed similar proportions of symptom resolution. With regards to ABS, clinical guidelines still recommend using FQs in certain cases where first-line treatments are contraindicated or have failed (4, fig.3). It is also worth noting that these new safety issues are based mostly on temporal associations from analysis of surveillance data which cannot conclusively determine causality – this is why further study of FQAD is warranted. The medications affected by these recommendations include: ciprofloxacin (Cipro™), gemifloxacin (Factive™), levofloxacin (Levaquin™), moxifloxacin (Avelox™) and ofloxacin (Floxin™) and norfloxacin (generic only) in Canada.

Despite the passing of the 1994 Dietary Health Supplement and Education Act, the marketing of dietary and natural products has continued to strain the consumer’s credulity while simultaneously seemingly staying at an arm’s length of the Federal Trade Commission’s and the Food and Drug Agency’s legal reach (1,2,3). In fact, since the passing of the act the industry has seen an exponential growth as the estimated number of supplements products increased from 4000 in 1994 to at least 55 000 in 2012 (4). In Canada, the situation isn’t any better.

A history of the DHSEA’s implications to the consumer’s health, and less importantly their pocketbook, is out of the scope of this post. However, great reviews can be found here and here for a Canadian perspective. The simplest way to put it is that contrary to prescriptions and over-the-counter (OTC) medications, supplements have a lower standard of safety and efficacy because they operate in a legal gray area where a multibillion industry can literally sell first and test later – if at all (5). The impact of dietary supplements on the consumer’s health are highlighted in a study by Geller et al. by the New England Journal of Medicine (4), which is subject of a today’s post.

Objective and Methods

The investigator’s objective was to “use a nationally representative surveillance data from 63 emergency departments obtained from 2004 through 2013 to estimate visits to U.S. emergency departments due to adverse events related to dietary supplements, and to identify and describe the associated characteristics of the patients, products and types of adverse event”.

This study is an analysis using the Adverse Drug Event Surveillance database system (NEISS-CADES)(6) conducted by the CDC, FDA and the Consumer Product Safety Commission (among others). Trained investigators looked at cases where the treating physician attributed emergency visits to to the use of dietary supplement(s). Products included were:

The reason for the use of supplements and also the adverse events were categorised. Those events were characterized as adverse reactions, allergic reactions, excess doses, unsupervised ingestion by children, or other events (e.g., choking). Deaths and intentional self-harm were not included at all in this study. Cases involving death were excluded because death registration practices vary widely between hospitals, and details are often lacking. Visits involving intentional self-harm, drug abuse, therapeutic failures, nonadherence, or withdrawal were also excluded.

Results

Visits: The authors retrieved a total of 3667 cases and estimated a rate of 23 005 (*) emergency departments visits per year attributable to dietary supplement adverse event and 2154 hospitalizations annually. More than half of the visits were from female and caucasian; more than a quarter (28.8%) of emergency department visits attributable to a supplement-related adverse event were from individuals aged between 20-34 years of age; hospitalizations for elderly patients were twice as frequent as younger people (16.0% vs. 8.4% p=0.003); about 1 in 5 incidents involved accidental ingestion of supplements by children (less than 4 years old).

Products: A large majority of those ER departments visits was attributed to a single product (88.3%) as opposed to multiple products. After excluding accidental ingestion by children, 65.9% of ER visits were attributed to a single herbal or complementary nutritional product and 31.8% of cases were involved with a single micronutrient product. Weight loss and energy supplements were involved in 25% and 10% of the ER visits respectively.

Sex: While weight loss products were nearly twice as likely used in the female patients as opposed to men (30.4% and 17.6%, respectively), the latter group showed that 17.1% of them took sexual performance or bodybuilding products which were attributed to the ER visit (too few women to calculate rate).

Age: About two thirds (67%) of children under four and elderly patients (65 years old and above) in this study had micronutrients as the suspected agent which commonly included iron, calcium and potassium; conversely, at least half of the 5-19 and 20-34 year olds had their visit attributed to either a weight-loss or energy product.

Figure: Notice the difference in patterns of the color proportions in each age groups: Weight loss/energy supplements (purple and light orange/beige) take up a large proportion of the ER visit rates in young adult (20-34 yo) while heart health/potassium (dark orange), calcium (green) and iron (dark gray) supplements make up a large part of ER visit rates in older and elderly adults.

Chest pain, palpitations and tachycardia were most often caused by weight loss or energy supplements (71.8%) which were affecting a large proportion young adults 20 to 34 years old (58%). Also, cardiac symptoms were frequently caused by bodybuilding (48.9%) or sexual-enhancement products (37.3%). As for micronutrients products, swallowing problems (choking, pill-induced dysphagia or globus) most frequently caused emergency visits due to calcium supplements (54.1%), while abdominal complaints (nausea/vomiting/pain) were primarily attributed to iron or potassium products.

Conclusion

This study shows from 2004 through 2013 in the United States, dietary supplements were implicated in 23 000 annual emergency department visits, of which about 1 in ten cases (2154) were serious enough to require hospitalization. Additional findings suggests that young and otherwise healthy adults (20-34 years old) were frequently presenting with cardiac symptoms (tachycardia, palpitations, chest pain) due to supplements used for weight loss, energy or bodybuilding purposes; children under 4 years of age were brought to ER departments with accidental ingestion of supplements (even with the supposedly child-proof iron products); older adults also commonly presenting with swallowing problems due to micronutrients (calcium, potassium,iron, etc).

Although, the study design (retrospective, cross-sectional surveillance database review) makes it somewhat difficult to determine causality between the specific supplement(s) and adverse events(s) beyond other confounding factors, their findings are still valid as they’re reasonably supported by the treating physician’s clinical suspicion. In other words, the supplements may not always have been the lone cause of the emergency visit, but are most probably the main cause or at the very least a major risk factor. However, this study does not speak to non-emergency settings, like outpatient clinics by specialists or primary care practices, nor to supplement-related deaths.

Even though the database used a validated and representative sample of US hospitals and minimum rate estimates were predicted beforehand, some rare adverse events may have not occurred frequently enough to have a statistically accurate annual estimation and this study did not try calculate for such events. On the other hand, this type of study is still more accurate than the current voluntary reporting of adverse events by supplement manufacturers (4). Clinicians should then use caution by relying on other evidence (7,8,9,10), or services (11), and their judgement to ascertain whether any supplement causes adverse events or supplement interactions.

Other limitations of the study include the fact that patients often don’t disclose their supplement use to physicians for various reasons, the dearth of supplement safety data and the subsequent lack of knowledge by clinicians of the true risks of supplements – all of which could lead this study to underestimate the true risks of dietary supplements. With the many regulatory and manufacturing problems of these products, clinicians must always consider the possibility that supplements may be contaminated with toxic substances, adulterated with prescription medications or may not even contain any of the listed ingredients.

Take home points of this study

Dietary supplements are associated with 23 000 annual emergency department visits, of which about 1 in ten cases were serious enough to require hospitalization

FDA approves Pradaxa antidote (Praxbind):

The Food and Drug Agency (US) has approved the use of the first specific reversal agent for the new oral anticoagulant dabigatran (Praxbind ™) called idarucizumab (Praxbind ™). It was approved by the accelerated approval program in which regulators rely on surrogate data or intermediate clinical outcomes reasonably likely to result in clinical benefit to patients (1,2).

Pharmacology: idarucizumab is a humanized monoclonal antibody fragment (Fab) indicated for patients who are on dabigatran (Pradaxa) which need: 1) reversal of the anticoagulant effects for emergency surgery or urgent procedures, or 2) in the event of life-threatening or uncontrolled bleeding. Idarucizumab is specific antidote for dabigatran, with no effect of other anticoagulant or antithrombotic agents. Contains sorbitol (precaution in hereditary fructose intolerance).

Its mechanism of action is the binding of dabigatran and metabolites to the idarucizumab molecule with a higher affinity than the binding of dabigatran to thrombin, resulting in an reduction of unbound anticoagulant and reversal of the it’s effect on coagulation parameters (e.g., ecarine clotting time (ECT) and/or activated partial thromboplastin time (aPTT)). It immediately reduces the levels of unbound dabigatran and ECT in the blood, and also sustains this reduction for at least 24 hours of a single dose.In one preliminary trial in patients with uncontrolled bleeding, homeostasis was achieved in the majority of cases with one case of thrombotic event (3). Further results in bleeding patients are pending.

Dosage: two consecutive infusions (over 5-10 minutes each) or bolus IV injections of 2.5g each ( 2.5g/50ml solution vials ) totalling 5 g per dose; due to the underlying clotting disease and thromboembolic risk of temporarily stopping the anticoagulant, dabigatran can be re-initiated 24 hours after antidote or as soon as medically appropriate. No adjustment needed in renal insufficiency and no data exists on hepatic insufficiency or pregnancy/lactation.

Safety: side-effects observed from small sampled clinical trials are hypokalemia (7%), delerium (7%), constipation (7%), pyrexia (6%), pneumonia (6%), headache (5%). Precaution should be observed due to limited evidence for hypersensitivity reactions and thromboembolic events or otherwise uncommon/rare adverse effects (4). There is also limited evidence on the safety and efficacy of repeat treatment of idarucizumab.

Role in Therapy: cerebral vascular accidents (strokes) have an estimated yearly rate of nearly 800 000 new or recurrent cases in the US alone, of which 10% are classified as intracerebral hemorrhage (ICH). Oral anticoagulants have a 7-10 fold higher risk of spontaneous ICH. It has also been estimated that OACs may be related to nearly 12% of all ICHs with a mortality rate of around 50%.

The absence of a direct reversal agent (i.e.: beyond the inconclusive evidence and numerous limitations of PCCs, rFVIIa, FFP and hemodialysis, etc) had been a major disadvantage of the newer direct anticoagulant agents (DOAC) such as Pradaxa, especially as opposed to warfarin. But now with the first antidote being approved in the US and Europe (not yet approved in Canada as of this writing) should help substantially decrease the rate of sudden dabigatran-related ICHs, pending further studies.

New Updated Beers Criteria list

The American Geriatrics Society (AGS) has released its second updated version of the Beers Criteria (5), which is one of the most frequently cited reference tools in the field of geriatrics. The updated and expanded edition, developed by a panel of 13 geriatric and pharmacotherapeutic experts, features lists of potentially inappropriate medications or classes of medications to be avoided in older adults who are not in hospice or palliative care. The new edition also includes:

– new lists of select medications to avoid and/or for which dose adjustments are to be based on a patient’s kidney function

– updated Potentially Inappropriate Medication (PIM) statements based on the strength of evidence and strength of recommendation

Role of Beers Criteria list: This tool is intended to improve prescribing; educate clinicians and patients; prevent and reduce adverse drug events; and serve as a tool for evaluating quality of care, cost, and patterns of drug use of older adults and elderly people. It is not intended to be used in a punitive manner nor to deny coverage to patients by medical insurance companies. Its stated goal is “ to improve the care of older adults by reducing their exposure to PIMs”.

It is a useful tool for all practicing clinicians caring for ambulatory, acute care and institutionalized settings of people of 65 years of age or older. It is not, however, a complete and comprehensive list of inappropriate medications since such a list would be too exhaustive, and therefore only meant as a clinical decision-making tool to be used in conjunction with practitioners’ own expertise and judgement.

The AGS has also published additional material including guides on how to use the Beers Criteria tool; teaching slides; numerous patient resources; and pocketcards available through free subscription or purchase (6).

Surveys show that Canadians find pharmacists to be the most trusted professionals, followed closely behind by physicians (1). When we also consider that most Canadians live within 2 to 5 kilometers of a pharmacy (2,3) and that pharmacists are medication experts who are an essential part of the health care team, why not “use” us to your advantage?

Instead of looking up drug information on the internet – which is a highly innaccurate source of medical knowledge – drop in to your pharmacy or give us a call and ask us! We don’t bite. In fact, it’s one of the most favorite part of the job for a lot of pharmacists: talking to you about your medications and healthcare needs! In fact, the pharmacy/dispensing fees’ general purpose is to pay for this service. The following is an incomplete list of questions every patient or caregiver should never hesitate to ask a pharmacist. Remember, there is no such thing as a stupid question so fire away!

“Are you the pharmacist? Can I talk to you in private?”

Most of the people who you see behind the prescription counter are not pharmacists, but everyone should have a name tag with their title. However, feel free to ask if they are one in case you can’t make out the small lettering. You may have to wait, but every pharmacy must legally have a pharmacist on duty to talk to you privately about your health.

Ask for a callback if he/she is tied up and you can’t wait. Also keep in mind that pharmacy assistants/technicians are able to answer some of your questions (those deemed technical like prescription refills, those concerning medical supplies like blood sugar meters, etc.) but always ask a pharmacist for specific medical questions.

“I don’t understand/know/agree why I need to take this medication”

A patient may often not know why he/she needs to take one or all of the medications that their physician/nurse practitioner orders. Sometimes they are so busy that they either forgot to explain, they did explain but the patient forgot, or they expect the pharmacist to do the explanation. It’s not a reproachable mistake on their part since they occasionally do this because of their obligation to other patients: they have to move on to their next appointment/task once the medical issue of the previous patient has been addressed. Besides, we pharmacists are more than able to educate the patient on the benefits – and risks – of one or a combination of drugs.

We have spent 5 or more years studying about all the benefits/risks of nearly all medications. When the benefits are less obvious, we can explain the reasoning behind certain prescriptions to reinforce your trust in the treatment plan; we can also recommend a more appropriate medication for you that the prescriber may have initially written; and we can even make sure that any worthwhile medication options haven’t been overlooked. Rarely, we may even have knowledge about a medication that the prescriber doesn’t fully appreciate yet (like newly discovered drug interactions or contraindications).

What are the side-effects of this/these medication(s)?

It is always important for patients to have a basic understanding of the possible risks involved with all medications. Patients often don’t bother to ask questions and instead rely on package inserts that come with their prescriptions (or look it up on the internet). In Canada, regulations require those drug inserts to contain information on most serious and some self-limiting side-effects – those not necessarily needing urgent medical attention – and typically don’t give any detail on how likely a person will develop those side-effects (common vs. rare). This is because regulators want those inserts to be easily understandable at the grade 6 to 8 reading level.

Importantly, those medication inserts do not contain “all the possible side effects you may feel…If you experience any side effects not listed here, contact your healthcare professional”(4). Your pharmacist is arguably the most convenient AND trusted source of information on potential side-effects and also what to do if you experience them because we are trained to manage those problems and to contact your physician/nurse practitioner if it is needed. In some healthcare organizations, pharmacists with additional expertise (like a “blood thinner” specialist) have additional training to manage certain medication issues without contacting a physician beforehand.

“How should I take this medication?”

Out of every 100 prescriptions written, only about 25 to 30 are taken properly. This is important because a lot of medications are useless if they’re not taken exactly as required. In medical terms, adherence means “The extent to which a patient’s behavior (in terms of taking medication, following a diet, modifying habits, or attending clinics) coincides with medical or health advice.” (5,6). However, being adherent to a treatment plan is one thing, but for patients to completely understand how they’re supposed to take a medication is an another problematic issue that pharmacists are keenly aware of.

Poor adherence is a huge problem since it causes a lot of preventable harm and extra strain on the health care system. In the United states, nonadherence accounts for 10% to 25% of hospital and nursing home admissions costing the American healthcare system 100 to 300 billions US dollars per year, and is also estimated to cause 125,000 deaths annually (7-9). The solution requires extensive communication and education with patients – which pharmacists are in an ideal position to do – so they know all the relevant information on how to take their medication to see their intended benefits. Some important information to know are:

the frequency

time(s) of day

relation to meal/food/drinks/exercise

relation to other medications/over the counter medications

the duration of the treatment, etc.

“Could these symptoms be caused by this medication and, if so, what should I do?”

The last thing I want to highlight is how pharmacists can help identify and manage side-effects that you may have. Some side-effects are temporary and go away by themselves days to weeks after starting the offending medication (s), while others can happen at any time or worsen as time progresses (e.g.: stomach ulcers due to anti-inflammatories). Some side-effects may be unapparent to the patient but can actually be a medical emergency (e.g.: closing of the throat after taking an antibiotic).

However, side-effects are generally moderate in severity which don’t usually require urgent medical care and, in most situations, they can be managed by talking to your pharmacist. Once he/she assesses your situation and determines that a patient is suffering from a side-effect, he/she will tell you what to do (e.g.: stop taking medication immediately or continue) and may contact your family physician and/or the original prescriber for follow up or various other reasons.

Conclusion

Nearly everyday I see patients experiencing non-urgent but troublesome side-effects that I think should be known to the physician and tell the patient to book an appointment with him/her to resolve the situation (e.g.: when a blood pressure medication needs replacing because of constant coughing). Fortunately, urgent medication problems are relatively uncommon (10). But I believe that “using” more extensively community pharmacists as trusted medication experts within a strong health care network (by increasing collaboration with physicians, hospitals, nurses, etc) can help to keep patients safer, healthier and out of hospital emergencies.

Remember when I wrote that extensive education is required for patients to be adequately adherent to their medications? Well, because medicine has become increasingly complex in the last few decades, most major medication issues can’t be addressed by pharmacists over a 5 minute discussion at the prescription counter. Fortunately, governments are finally realizing the importance of pharmacists and are paying us to provide multiple in-depth consultations (e.g. medication reviews) lasting anywhere from 15 to 60 minutes (private medication insurance is lagging in this respect). I will definitely write about medication reviews on a future date because I believe it is a very important service we provide for patients at high-risk of medication errors.

Pharmacists are ready to have a bigger presence in your overall health by allowing us to manage your medication issues more directly to prevent you from suffering from a drug related problem. All you have to do is ask!

Everybody has seen the subtle ads on television about erectile dysfunction (ED) which you might have mistakenly thought it was advertising an impossibly effective antidepressant. Or maybe something about not washing vintage cars? Anyway, more men are in or approaching their golden years and this trend increases the co-prevalence of two common medical conditions: heart disease and ED. The latter is a serious sexual problem which not only contributes to psychological and interpersonal problems, but also is an important predictor of mortality, cardiovascular death, myocardial infarction (MI) and congestive heart failure (CHF) in men with coronary artery disease (CAD).

Erectile dysfunction is easily treated with a handful of very effective drugs called phosphodiesterase-5 inhibitors (PDE5I): Viagra (sildenafil), Cialis (tadalafil) and Levitra/Staxyn (vardenafil). One absolute contraindication of PDE5Is is using nitroglycerin products. I learned in pharmacy school that this combination is a definite no-go and a call to the physician was in order. However, I have recently noticed that despite the contraindication, I have seen more than one physician waive this contraindication for CAD patients who have rescue sublingual nitroglycerin. So I decided to do an in-depth review of the evidence supporting the interaction while also trying to find evidence-based recommendations to guide the safe use of PDE5-inhibitors in CAD patients.

Prime Suspects: Blockbuster PDE5-Inhibitors and Nitrates

Clinicians were initially cautious when using PDE5-I in certain patients with heart disease. Now we know we can generally use them safely in certain patients who are considered low-risk of cardiovascular event due to resumption of sexual activity (1,2). It is important to note that anyone with cardiovascular disease (e.g.: CAD, CHF) should first consult their physician for an evaluation as to whether one can resume sexual activity because this level of exertion increases the chance of suffering a cardiac or vascular event (e.g..: heart attack or stroke). Of course it is important to rekindle your love life, but make sure to get the green light from your doctor first.

PDE5-inhibitors are effective and generally safe to use as indicated and they are very frequently prescribed to patients with little tolerability issues. Common side effects (rate: 1 out of 100: dyspepsia, nasal congestion or rhinitis, dizziness, visual disturbances, flushing,headaches or myalgia) are minor and reversible. There are, however, post-marketing reports of hearing loss and non-arteritic anterior ischaemic optic neuropathy (NAION) causing sudden loss of vision in patients taking PDE5 inhibitors, but there’s little evidence as of yet that they conclusively cause either hearing or vision (3,4) loss. There are also a few reports of priapism related to the use of sildenafil in overdoses but also in patients who took normal doses (5). Sudden loss of vision or hearing, and having an erection of more than 4 hours following any PDE5-inhibitors are medical emergencies and should be treated as soon as possible.

Nitrates typically are indicated for acute symptomatic relief of chest pain (due to angina or MI) or for long-term management of stable CAD (e.g: daily use). These includes nitroglycerin or glyceryl trinitrate in the form of patches, ointments, sublingual tablets/spray or injections; isosorbide dinitrate and isosorbide-5 mononitrate as regular or sublingual tablets. Nitrates are life-saving drugs and everyone who is prescribed these products should never go without them. Also important: rescue type formulations should be regularly checked to see if they are expired (due to loss of effectiveness) because they are only occasionally used and thus tend to outlast their expiry date.

Headaches are common side effect, and although they can appear in at least 50% of all patients who start taking nitrates, it is usually a minor problem and disappear within days to a week or so. Nitrate-related headaches can be treated with acetaminophen until resolved (6).

Mechanism of PDE5-Inhibitors – Nitrates Interaction

Physiologically, erections are initiated by a sexual stimuli which triggers endothelium-mediated vasodilation mediated by cGMP, which promotes trabecular and vascular smooth muscle relaxation. Sildenafil and it’s ilk distribute not just in the intended target, but also to platelets, veins, systemic arteries, lung and cardiac vasculature. Specifically, PDE5Is inhibit the breakdown of cGMP while nitrates increase the supply of cGMP; if taken together, they result in an excessive accumulation of cGMP which can cause severe vasodilation and hypotension (2,3,7).

Other important parameters to remember is that PDE5Is aren’t all hepatically metabolized the same way: tadalafil is the different one here in that it takes about 2 hours to act, is unaffected by fatty foods and lasts a full 36 hours due to CYP3A4 (100%) inactivation (T1/2=17.5h); sildenafil’s and vardenafil’s onsets of actions are both around 30 to 60 minutes, but longer if taken with a fatty meal ( yet act about 12 hours with metabolism shared by CYP3A4 (80%) and 2C9 (20%) (T1/2= 4-5h)). This is important clinically in terms of recommendations of PDE5I-Nitrate interactions. Other drug-PDE5I interactions are not addressed directly in this review (alpha-blockers, etc) and readers are to revise references 10 and 11 for an extensive overview of PDE5-inhibitor interactions.

CAD and it’s risk factors such as diabetes, hypertension and hyperlipidemia are all prevalent in patients suffering from erectile dysfunction (8). Fortunately, co-prescription of Nitrates and PDE5Is seems relatively low (3.3% in one study) but potentially could be lower because it may be that multiple prescribers are an important driver in a potentially dangerous PDE5I interaction (9). This provides a unique opportunity for community pharmacists to monitor this dangerous interaction, comprehensively inform the patient of the risks of nitrate-PDE5Is co-prescription and to resolve potential drug-related problems.

Recommendations

The American Heart Association and the American College of Cardiology have offered guidance on this clinical problem (10,11,12):

Nitrates can be administered only 24 hours (6 half-lives) after sildenafil intake to allow full clearance of the drug; Additionally, nitrates should be withheld for at least 48 hours after tadalafil intake; a low dose of PDE5Is should be initiated in patients with a stable dose of an non-selective (cardioselective; doxazosin) alpha-blocker.

It may be prudent to allow additional time to elapse in patients with conditions that increase plasma levels of PDE5Is

Use extra caution when using moderate to strong CYP3A4 inhibitors or inducers, dose adjustments may be required

Patients prescribed PDE5Is should be counseled to inform emergency workers and physicians about their most recent PDE5I intake so that nitrates can be avoided.

If a patient has taken a PDE5I, receives a nitrate, and becomes hypotensive from pronounced vasodilation, it is suggested to place the patient in the Trendelenburg position; treat with aggressive fluid resuscitation, and if necessary an beta-agonist (phenylephrine), alpha-agonist (norepinephrine), and intra-aortic balloon counterpulsation; there is no antidote to PDE5Is.

All other medications should be given if appropriate to the clinical condition, including the antianginal agents beta-blockers, calcium channel blockers, and morphine, as well as aspirin, statins, oxygen, thrombolytics, and antiplatelet agents as indicated.

Conclusion

Appropriate patient counselling of PDE5-inhibitors include discussion on life-threatening interaction with nitrates (and alpha-blockers) causing severe hypotension (less than 85 systolic mmHg) and also on the initial signs and symptoms; for example: severe headache, dizziness, or syncope. They should also be warned to avoid recreational inhaled poppers and nitroglycerin from friends and family, or black market or “natural” health products (e.g.: PDE5I-laced “traditional remedies”).

Only after documenting your communication with the prescriber(s) and patient that both clearly consent to the co-prescription of PDE5-inhibitors and nitrates should a pharmacist waive such interaction. Make sure the primary care provider is aware of the co-prescription and that the patient clearly understands the risks: if one takes a PDE5I and uses a rescue nitrate, one also needs to know that if they are suffering from anginal symptoms they may have to forgo one medication which is part of life-saving protocols (12). For a more detailed reading on these contraindications and other dangerous nitrate interactions refer to references 10 and 11.

One last point for pharmacists: given there is an estimated 3% co-prescription rate of PDE5I and nitrates – which means 1 out of every 33 patients taking a PDEI may also be taking a nitrate – a pro-active systematic search of pharmacy patient profile databases could easily investigate this potentially dangerous drug-related problem, especially in moderate to high-volume pharmacies.

We know you have busy lives. We know you come into our stores and are on your way to or from work, with kids waiting in the minivan or with your elderly mother waiting to receive their pain medication after getting out of surgery. We know you probably don’t have a lot of time to needlessly wait around. But the problem is pharmacists can’t work faster than a certain rate or workload without increasing the chance of a preventable medication error.

Pharmacies need to continually evolve with the growing amount of responsibilities that pharmacists face. The busier they are the more pharmacists have to better prioritize their work, and that involves taking more time to fill certain prescriptions while spending more time to remedy and prevent potential medication errors. Next time you cross a pharmacist, give them a big thanks for not rushing at their job. You will melt their hearts, trust me. The following are suggestions that should safely help you from spending too much time waiting for your prescriptions.

5 Tips to Follow Before Going to the Pharmacy

1 – Make sure you have a list of active medications and that it is regularly checked with pharmacist/technicians

If you take a medication occasionally or every day, it’s a very good idea to know it’s name and strength (e.g.: warfarin or insulin). It also helps to remember what time(s) during the day you take it because some medications are very specific. However, because people often need more than one medication to control their medical condition(s), remembering every medication can be a very difficult task to do. Fortunately, pharmacists are a clever bunch and have tools which can help!

Ask your pharmacist for a wallet/purse size paper list of all your medications andcarry it with you everywhere you go. You may have to use your reading glasses to read it, but they are very handy and a lot more practical than carrying all of your medication bottles with you at the physician’s office, for example. One last thing: you need to make sure it is constantly updated by either letting your pharmacy staff know if you’ve started or stopped taking any medication(s).

2 – Remember to bring in ALL your prescriptions that the doctor gave you on your last visits

Whenever you grab your keys to leave home for the pharmacy, ask yourself if you have any prescriptions tucked away somewhere from your recent visit to the doctor. Some people have tendency to hold on to their newest precriptions in order to “use up” their remaining refills on their old scripts. We know you may not always like the news when you go to your physician/nurse practitioner and some of you seem to hold off seeing him or her untill you really have to, but this is a potentially dangerous thing to do and can lead to medication errors which pharmacists are powerless to prevent.

This is because physicians have to monitor your health at certain intervals of time if you have chronic medical conditions, and one way they make sure you are following their recommendations are by prescribing medications for a specific amount of time. Another critical reason to not keep your new prescriptions like a squirrel hoarding nuts: often a physician will make a change in your medications and will either forget to tell you or, more likely, you will forget about the change. Do yourself a favor and drop off all of your prescriptions so we can make sure you’re getting the right medications every time.

3 – Double-check you are low on certain pills and roughly determine how much days you have left

Check all of your prescriptions to see how many pills or days you have left. If you have only about 2 or 3 days left of medications, then you usually are due to have them refilled (see tip #4). There are exceptions for controlled medications or any medications which the physician/nurse practitioner has set specific refill dates. It is actually illegal to fill a controlled medication (like certain sleeping pills, stimulants for attention deficit disorders or painkillers) too early – because of their inherent abuse potential – and pharmacists can be disciplined through their societies/boards if they don’t follow this rule.

If you call in a week or more ahead of its due date, sometimes your insurance (if you have drug coverage) won’t pay for the medications, controlled or not. That happens more often than you would think, and unfortunately the problem lies with your insurance company’s policy and pharmacy staff are powerless to help.

4 – Use an App, Email or Call in your Medication Refills Ahead of Time

All pharmacies have options for you to let us know which medications you want refilled so they’re ready for you to pickup without waiting. Ask your pharmacy’s staff if you can refill your medications by telephone, email, through the store’s website or through an app. For the latter two, make sure it’s a legitimate service (i.e.: official pharmacy chain app).

You can also have your refills renewed all at the same time – what’s called medication synchronization. Although you have to talk to your pharmacist or their assistant to make sure it is done safely, it can be an helpful way to organize your time, make less frequent trips to the store and help with medication adherence.

5 – Make sure you have your Insurance information

Insurance issues are often the cause of wait times at the pharmacy. If you changed jobs, if you started college or university, or if your boss announced that there are changes to you insurance coverage, it usually means that your prescription insurance information will change and your old card may not work. That’s why it is a good time-saving habit to always carry your valid prescription insurance with you in your purse or wallet.